Signaling the mitochondrial unfolded protein response

Abstract

Mitochondria are compartmentalized organelles essential for numerous cellular functions including ATP generation, iron-sulfur cluster biogenesis, nucleotide and amino acid metabolism as well as apoptosis. To promote biogenesis and proper function, mitochondria have a dedicated repertoire of molecular chaperones to facilitate protein folding and quality control proteases to degrade those proteins that fail to fold correctly. Mitochondrial protein folding is challenged by the complex organelle architecture, the deleterious effects of electron transport chain-generated reactive oxygen species and the mitochondrial genome's susceptibility to acquiring mutations. In response to the accumulation of unfolded or misfolded proteins beyond the organelle's chaperone capacity, cells mount a mitochondrial unfolded protein response (UPR(mt)). The UPR(mt) is a mitochondria-to-nuclear signal transduction pathway resulting in the induction of mitochondrial protective genes including mitochondrial molecular chaperones and proteases to re-establish protein homeostasis within the mitochondrial protein-folding environment. Here, we review the current understanding of UPR(mt) signal transduction and the impact of the UPR(mt) on diseased cells. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids.

Figure 1. Model of the mammalian UPR^mt signaling pathway

Activation of the UPR^mt in mammalian cells occurs in response to stress originating from the mitochondrial matrix or the intermembrane space (IMS), each having distinct signal transduction pathways and transcriptional responses. Accumulation of unfolded proteins within the matrix stimulates the transcriptional up-regulation of the transcription factor CHOP via JNK2 and c-Jun [57, 62]. CHOP subsequently activates the transcription of genes including the quality control protease ClpP and the chaperonin Hsp60 [58]. Alternatively, accumulating unfolded proteins in the IMS causes activation of the kinase AKT and phosphorylation of the estrogen receptor (ERα) leading to the transcriptional up-regulation of the IMS protease Htra2 and the transcription factor NRF1 [64].

Figure 2. Model of the C. elegans UPR^mt signaling pathway

UPR^mt signaling is initiated as unfolded proteins accumulate beyond the resident chaperone folding capacity. To prevent protein aggregation, unfolded or misfolded proteins are degraded to peptides by the quality control protease ClpP in the mitochondrial matrix [68]. HAF-1-mediated peptide efflux leads to activation of the bZip transcription factor ATFS-1 that accumulates in the nucleus. HAF-1-mediated peptide efflux is also required for the accumulation of the ubiquitin-like protein UBL-5 which complexes with the transcription factor DVE-1 [69]. ATFS-1 and DVE-1/UBL-5 then cooperatively induce the expression of mitochondrial chaperone genes including Hsp60 and mtHsp70 in order to restore protein homeostasis.

Figure 3. Proposed relationship between the UPR^mt, mitophagy and apoptosis during mitochondrial stress

Mitochondrial stress and dysfunction result in the activation of at least three cellular responses including the UPR^mt, mitophagy and apoptosis. We propose the depicted relationship between the three pathways as a function of mitochondrial stress level or the duration of mitochondrial stress. Because the UPR^mt is a mitochondrial protective response activated to re-establish homeostasis within stressed organelles and mitophagy removes severely defective mitochondria with a completely dissipated inner membrane potential, we propose the UPR^mt is activated at lower levels of stress or prior to the induction of mitophagy. As stress in individual mitochondrion exceeds the cytoprotective capacity of the UPR^mt, mitophagy eliminates the dead organelles. However, if the total cellular mitochondrial damage becomes too great the cell may undergo apoptosis.